Chronotherapy with 5-fluorouracil, folinic acid and carboplatin for metastatic colorectal cancer; an interesting therapeutic index in a phase II trial

The aim of this study was to develop a Phase II study gauging the contribution of a daily low-dose of carboplatin combined with 5-fluorouracil (5-FU) and folinic acid (FOL) in a chronotherapy schedule for advanced colorectal cancer patients. GO patients with metastatic colorectal cancer were included in a phase II trial in which 50% of patients had received prior chemotherapy of up to three regimens. Treatment consisted of a combination of 5-FU (700 mg/m(2)/day) and FOL (300 mg/m(2)/day) infused from 10.00 pm to 10.00:im peaking at 4.00 am with carboplatin infused from 10.00 am to 10.00 pm at 40 mg/m(2)/day with a peak at 4.00 pm. 4-day courses were repeated every 2 weeks in an ambulatory setting with a programmable pump. Patients experienced excellent tolerance (grades III-IV%): diarrhoea, 8.1; nausea:vomiting, 4.8; mucositis, 3.2; skin or neurological 1.7; granulocytes 29.0; platelets and haemoglobin (Hb) 9.7. Major tumour responses were observed in 47% of cases. 4 complete response (CR), 24 partial response (PR); 3 CR and 6 PR (69%) were recorded in 13 previously untreated patients, 11 (18%) underwent subsequent surgical resection of residual metastases. Median survival was 14.6 months with 22% patients surviving over 3 years (35% survival for responders versus 0 for non-responders). In conclusion, this chronotherapy determined administration of 5-FU/FOL and carboplatin yielded an excellent therapeutic index for the combination and warrants further evaluation ill the first-line treatment of metastatic colo-rectal cancer. (C) 2000 Elsevier Science Ltd. All rights reserved.